Appraisal , Work-Up and Diagnosis of Anterior Uveitis : A Practical Approach

The diagnostic yield in uveitis has significantly improved in the last 15 to 20 years, in part because a clear classification is available to the clinician but even more so because diagnostic tests have greatly improved lately. With a systematic approach, based on history and clinical examination and guided by laboratory tests and other investigational tests, a diagnosis can be expected in about 70% of cases. A compilatory approach, as exposed in most uveitis textbooks, has to be avoided [Figures 1a and b]. The endless lists of disease, exposure which the patient is supposed to tick on a check-list do not contribute to a diligent work-up of uveitis and are even counterproductive as this may push the clinician in the wrong direction.


Introduction
The diagnostic yield in uveitis has significantly improved in the last 15 to 20 years, in part because a clear classification is available to the clinician but even more so because diagnostic tests have greatly improved lately.
With a systematic approach, based on history and clinical examination and guided by laboratory tests and other investigational tests, a diagnosis can be expected in about 70% of cases.
A compilatory approach such as it is exposed in most uveitis textbooks has to be avoided.(Figure 1a & 1b) Endless lists of diseases the exposure to which the patient is supposed to tick on a checklist are not contributing to a diligent work-up of uveitis and are even counterproductive as this may push the clinician into the wrong direction.

Fig. 1a & 1b Example of the traditional lists that are featured in most uveitis books
It is much more productive to use a comprehensive approach that avoids a detailed anamnesis (history) at the beginning of the consultation but limits the initial anamnesis (history) to the immediate complaints of the patient followed immediately with a thorough clinical examination.Once the the clinical signs have been established and have allowed to characterize the type of uveitis (granulomatous versus non-granulomatous) the anamnesis (history) can be resumed by asking oriented questions.The clinician should then try to classify the uveitis more precisely, refer to the local epidemiological data and come up with a working diagnosis, which he should always be prepared to change.At this point targeted investigations and laboratory tests should be performed.The result is a diagnosis which has higher degree of probability that can be followed by appropriate therapy.In case no dignosis can be suspected non specific therapy may have to be started or therapy can be withheld.In a proportion of cases the evolution of the disease will lead to the diagnosis.(Flow-chart 1)

Definition
The anatomical classification of uveitis into anterior, intermediate and posterior forms is very useful to conduct the work-up and eventually to reach a diagnosis, even though inflammation does not always respect these anatomical boundaries.Anterior uveitis is the term used for the group of inflammatory disorders for which the preponderant part of the inflammation is situated at the level of the pars plicata of the ciliary body, the retroiridal space, the iris and the anterior chamber.

Symptoms and signs of anterior uveitis
The severity of symptoms in anterior uveitis ranges from no symptoms in chronic disease such as anterior uveitis related to juvenile idiopathic arthritis (JIA) to very severe symptoms in acute uveitis such as HLA-B27 related uveitis.Symptoms of acute anterior uveitis include photophobia, redness, pain, decreased vision and tearing in the absence of discharge.
The signs of anterior uveitis are listed in table 1 ____________________________________________________________________ Table 1.Signs of anterior uveitis.1.The conjunctival injection in anterior uveitis can be diffuse or localized circumferentially at the limbus (perikeratic injection) or mixed (diffuse and perikeratic injection).
2. The morphology of keratic precipitates (KPs) is very useful to help distinguish non-granulomatous from granulomatous uveitis.Small diffuse KPs causing dusting of the endothelium are characteristic for nongranulomatous uveitis such as HLA-B27 related acute anterior uveitis.When KPs become larger than endothelial dust they can be individualised and correspond to granulomatous KPs.The morphology and distribution of granulomatous KPs is often useful in orienting towards a more specific diagnosis within granulomatous causes (table 2).Medium and large size KPs are called "mutton fat" KPs.There is a lot of confusion regarding the characterisation of KPs.In many textbooks only mutton-fat KPs are termed granulomatous and small granulomatous KPs as those found in Fuchs' uveitis are erroneously termed as non granulomatous.Therefore Fuchs' uveitis is mistakenly classified as non-granulomatous in many textbooks.It is useful to distinguish between fresh and chronic (old) muton-fat KPs.Old mutton-fat KPs tend to be less white, pigmented and less dense in the centre.

Table 2. Granulomatous keratic precipitates (KPs)
Type of KP Clinical entity to suspect Small stellate, even distribution no gravitation Fuchs' (heterochromic) uveitis (Figure 6) Small gravitational or inferior random distribution CMV uveitis (Figure 7) Small/medium/ size, focal spherical distribution under stromal keratitis h.simplex/zoster keratouveitis (Figure 8)     When the quantity of cells is very dense they sediment and cause a hypopyon, a sign more often seen in HLA-B27 related uveitis, Behçet's uveitis and uveitis related to juvenile idiopathic arthritis (JIA).(Figure 4) 6.In severe and longstanding uveitis iris rubeosis can develop.It is in fact most often a pseudo-rubeosis that is reversible after introduction of anti-inflammatory treatment.Even when a real rubeosis has developed, it is usually situated at the pupillary border of the iris and is much less agessive and proliferative than ischemic rubeosis iridis.In Fuchs' uveitis with extensive iris atrophy iridal vessels can be seen and correspond to a pseudo-rubeosis.

Iris nodules (Figures 5a & 5b)
In granulomatous uveitis two types of iris nodules can develop.When situated at the pupillary margin (and on the surface of the iris) they are called Koeppe nodules, have a fluffy appearance and a size going from very small barely visible excresences to frank nodules.When nodules are situated in the body of the iris stroma they are called Bussaca nodules.
8. Sectorial or widespread iris atrophy is a sign rather specific for herpes simplex or herpes zoster uveitis and is a useful diagnostic help.Diffuse atrophy is very often seen in Fuchs' uveitis.

Intraocular pressure changes due to uveitis can present either as hypotension or hypertension.
Hypotony is usually measured in severe uveitis involving the ciliary body such as acute anterior nongranulomatous HLA-B-27 related uveitis.Hypertony is usually associated with granulomatous uveitis, especially herpes simplex or herpes zoster uveitis but also sarcoidosis or spill-over anterior uveitis associated with toxoplasmic retinochoroiditis.In recent years, CMV anterior uveitis, a newly recognised usually unilateral entity very often causing hypertony has been described.3 The work-up of anterior uveitis The anatomical diagnosis of anterior uveitis has first to be verified by excluding spill-over inflammation associated with uveitis of the posterior segment (intermediate or posterior uveitis).To exclude posterior involvement pupil dilatation is mandatory in all cases.Secondly, the type of clinical presentation has to be characterized as non-granulomatous or granulomatous in order to correctly orient work-up and differential diagnosis.
Non-granulomatous uveitis is characterised mainly by the type of keratic precipitates that presents as fine KPs producing endothelial dusting.In severe cases fibrinous clotting or hypopyon can occur depending on whether protein influx or cellular infiltration is predominant.In case of severe inflammation it is also common to find posterior synechiae and pressure tends to be more often decreased than increased.Although this distinction is a very useful working classification, the subdivision is not an absolute one.A granulomatous uveitis may initially present as non-granulomatous when dusty KPs are very thick so that before taking its granulomatous aspect.Conversely in rare cases a non-granulomatous uveitis can take an aspect that might be qualified as granulomatous.In most cases the distinction is however rather well delineated ____________________________________________________________________

Work-up of non-granulomatous anterior uveitis
In case of simple, fibrinous or hypopyon nongranulomatous uveitis, the only first-line work-up test we presently perform is the detection of the HLA-B27 antigen.HLA-B27 testing is performed even if the inflammation is only moderate.If the test is positive it will avoid further unnecessary testing during a subsequent episode and it is reassuring for the patient and the doctor to know the specific diagnosis, especially when it is a benign disease.In case of a positive result no further investigation is performed at the ophthalmological level.It is however recommended to take an oriented history that will allow, with the help of the internist or rhumatologist when necessary, to subclassify the affection into ankylosing spondylarhritis, Reiter's syndrome, Crohn's disease, ulcerative colitis or simply into HLA-B27 uveitis without systemic associated disease.About 50-55% of acute anterior non-granulomatous uveitis are HLA-B27 If the episode of HLA-B27 negative non-granulomatous uveitis is of limited severity and / or responds readily to classical topical corticosteroid therapy no further investigation is performed.In case of an anterior uveitis with hypopyon signs and symptoms found in Behçet's syndrome should be searched for, in particular oral and/or genital ulcerations, cutaneous signs such as erythema nodosum and pustules, arthralgies, thrombophlebitis or central nervous system involvement.If Behçet's uveitis is suspected we find it useful to look for the HLA-B51 antigen that, when present, represents an aditional argument for the diagnosis of Behçet's uveitis, especially in the milder forms of Behçet's uveitis seen in the european caucasian population.Isolated anterior Behçet's uveitis can occur but posterior involvement should be searched for by funduscopy and is best investigated by performing a fluorescein angiography looking for retinal vasculitis.

Flow
In case of non-granulomatous uveitis in children (with or without band keratopathy) history should be directed towards juvenile idiopathic arthritis (JIA).Inflammatory symptoms can be completely absent, contrasting with the severe signs of uveitis such as hypopyon and extensive synechiae that can characterise JIA related uveitis.Uveitis is usually associated with the pauciarticular form of JIA and testing should include anti-nuclear antibodies (ANA) that are present in up to 70% of JRA patients with uveitis.In elderly children it is also useful to test for the presence of HLA-B27 antigen.
A bilateral non granulomatous uveitis in children, but also in adults, should prompt to search or exclude tubulointerstitial nephritis and uveitis syndrome (TINU), an often neglected diagnosis.Renal function should be tested, starting with the dosage of creatininemia requiring sometimes renal biopsy and urinalysis should be performed looking for glucosuria and dosage of beta-2-microglobulin which is found to be elevated inTINU.5 In children pars planitis can initially present with a pronounced anterior participation and can be mistaken for an anterior uveitis if the posterior segment is not carefully analyzed.
In case of non-responding HLA-B27 negative anterior uveitis or in case of recurrence we pursue the workup in the same fashion as for a granulomatous uveitis

Work-up of granulomatous uveitis
Before starting the work-up of granulomatous uveitis, it is important to exclude Fuchs' heterochromic uveitis because this condition, when sufficiently typical, does not need any work-up.Furthermore corticosteroid treatment should be withheld in Fuchs' uveitis to avoid the side-effects of a treatment that usually has no impact on the inflammatory process.Characteristic findings of Fuchs' uveitis include fine stellate granulomatous keratic precipitates that usually do not accumulate inferiorly by gravitation but are more uniformly distributed over the whole surface of the endothelium,( Figure 6) fine Koeppe nodules at the pupillary edge of the the iris, prominent vessels in the irido-corneal angle seen by gonioscopy and absence of posterior synechiae.Heterochromia is only present in fair-coloured irises but not in dark irises.Therefore the name of this entity should not include any more the term of heterochromic and should simply be called Fuchs' uveitis.It should be kept in mind that involvement can be bilateral.Laser flare photometry shows a very moderate breakdown of blood-aqueous barrier of 10.2±3.5 ph/ms (normal 3.5-4.0ph/ms) that rermains relatively stable over time and ususally does not respond significantly to anti-inflammatory treatment.
Spill-over anterior granulomatous uveitis as it can occur in very inflammatory toxoplasmic retinochoroiditis has to be excluded by performing a detailed examination of the posterior segment with funduscopy.

Granulomatous uveitis : systematic diagnostic approach 1
Step 1 exclude Fuchs' uveitis Toxoplasmic retinochoroiditis can sometimes present as a granulomatous (hypertensive) anterior spill-over uveitis.The presence of a retinal focus orients clearly into this direction.In order to make the diagnosis possible toxoplasmic serology should be performed shown simply the presence IgG antibodies indicating that the patient has been in contact once in his life with Toxoplasma Gondii.
suspected.Clinical signs that are very suggestive of herpes simplex / zoster uveitis are ocular hypertension and iris atrophy (found both in herpes simplex and varicella-zoster uveitis).Laboratory confirmation of herpes simplex / zoster anterior uveitis can be obtained by the detection of intraocular production of antibodies in the aqueous humor (Goldmann-Witmer coefficient).Aqueous paracenthesis is however not performed routinely in these cases but reserved for sight-threatening diseases such as necrotic herpetic retinopathies (NHR) that include acute retinal necrosis.It is also performed in uveitis suspected to be herpetic but that does not reapond to classical combined systemic antiviral and topical antiviral therapy to detect CMV DNA in the aqueous.
A condition that can be associated with anterior granulomatous uveitis is multiple sclerosis (MS).In most cases postrior segment findings such as priphlebitis and vitritis are usually present.In patients with a history compatible with MS investigations should be directed towards MS beginning with a cerebral MRI.11

Figure 3 .
Figure 3. Posterior irido-lenticular synechiae.The ring of pigment deposits on the cristalline lens show where the iris was attached (synechiae).There is one remaining synechia at six o'clock on the verge of detaching itself following the administration of massive dilating drops.

Figure 4 .
Figure 4. Hypopyon.Sedimented white cells form a level at the bottom of the anterior chamber, associated with a ring of fibrine on the surface of the cristalline lens (top) indicating broken synechiae.One remaining synechia on the meridian of 7 o'clock.

Figure 5a .
Figure 5a.Koeppe nodules.Two Koeppe nodules at the border of the iris associted with synechiae.

Figure 5b .
Figure 5b.Busacca Nodules.UBM picture showing nodule within the stroma in a patient with tuberculous uveitis.

Figure 7 .
Figure 7. KPs in CMV anterior uveitis.Scarce unilateral KPs of different sizes (small to medium) in a case of cytomegalovirus (CMV) anterior uveitis.

Figure 8a .
Figure 8a.Herpes KPs.Usually herpes/zoster KPs are arranged in a round disciform pattern and are small to medium sized..

Figure 8b .
Figure 8b.Herpes KPs.Usually arranged in a round disciform pattern very well visible against retroillumination.Note also sectorial iris atrophy at the top of the picture at the level of the superior iris.

Figure 9 . 3 . 2 ) 4 . 4 ) 3 .
Figure 9. Mutton-fat KPs.This type of gravitational large KPs can be seen in tuberculosis and sarcoidosis.In toxoplasmosis the anterior inflammation sometimes associated with the retinitis is also made of large mutton-fat KPs, although the KPs are usually less numerous.

Table 5 .
Common causes of non-granulomatous anterior inflammation in anterior uveitis or panuveitis HLA-B27 related uveitis Behçet's uveitis Juvenile rhumatoid arthritis related uveitis Uveitis associated with scleritis Uveitis associated with streptococcal infection ____________________________________________________________________ Granulomatous uveitis is characterized by KPs that are larger than the dusty KPs of non-granulomatous uveitis.They are better individualized but their size varies depending on the inflammatory process.The medium and large size granulomatous KPs are called mutton-fat KPs.(Figure 9) Other characteristic features of granulomatous uveitis are Koeppe and Bussaca nodules.(Figures 5a & 5b) Synechiae are common in more pronounced inflammation.Pressure changes when present are usually characterized by increased intraocular pressure.

Figure 10 .Flow
Figure 10.Laser flare photometry.This machine is measuring the content of proteins in the anterior chamber and hence the level of inflammation in an objective and quantitative fashion.The instrument shines a laser into the anterior chamber and the electronic detector is counting the number of photons that are back-scattered.Back-scattered photons are proportional to the amount of particles (proteins) and hence proportional to the intraocular inflammation

• small stellate KPs, non gravitational, regularly distributed over the cornea • vitreous infiltration • usually unilateral • Koeppe nodules possible • polar posterior cataract • heterochromia Step 2 : first-line lab. tests Lysozyme (L) Angiotensin converting enzyme (ACE) Tuberculin skin test Multiple herpetic serologies (polyclonal activation) Serum L & ACE elevated DTH anergy Herpetic serologies show polyclonal activation Serum L & ACE elevated Mantoux®/PPD skin test/TB +++; γ-IFN- releasing assays + Tuberculosis probable
The first-line laboratory tests performed to investigate granulomatous uveitis are serum angiotensine converting enzyme (ACE) and lysozyme, products indicating the presence of granulomatous lesions.ACE can be normally elevated in children and serum lysozyme levels tend to be progressively more elevated in elderly persons.It is therefore important to perform both tests.The second step is to differentiate between sarcoid, tuberculous or other granulomatous causes.In order to differentiate between tuberculosis and sarcoidosis, multiple skin tests, measuring delayed type hypersensitivity reaction to several antigens to which the adult patient should be normally reacting (MultiMérieux® containing tuberculin, streptococcus, diphteria, tetanos, tricophyton and candida antigens) are performed to search for anergy, a strong argument for sarcoidosis.This test is however rarely performed nowadays as the Merieux® multi-antigen applicator is difficult to find.In a patient vaccinated for tuberculosis or that is known to have been exposed to a tuberculous infection a PPD skin test that has become negative has the same diagnostic value.We find it also useful to look for polyclonal antibody activation that is present in up to 85% of the patients with sarcoidosis 6,7 and was also found in patients with ocular sarcoidosis.8 For this purpose, serologies to four herpes viruses to which most of the adult population has been exposed (herpes simplex, herpes zoster, cytomegalovirus and Epstein-Barr) are On the other hand when the PPD tuberculin skin test is hyperpositive this should raise the suspicion of a tuberculous granlomatous uveitis.Nowadays the next test to be performed is one of the gamma-interferon releasing assay that are testing blood lymphocytes of patients in order to detect whether there are lymphocytes reacting in vitro when put in presence with specific proteins coming from Mycobacterium Tuberculosis.When the patient's lymphocytes release gamma-Interferon, it means that the patient has been exposed to the bacteria and tuberculosis should be actively researched.10 BAL = bronchio-alveolar lavage ; DTH = delayed type hypersensitivity ; Ga-scan = galium scan ; IFN = interferon; TB = tuberculosis performed.ELISA serology detects exposure to these viruses and complement fixation serology is done to establish whether the antibody titers are elevated.An isolated elevated titer to one virus only might be indicative of a viral etiology.Polyclonal activation however is an additional element for sarcoidosis.This non-specific antibody elevation is the cause of some of the false-positive diagnosis of presumed infectious uveitis, relying only on a serology such as Lyme borreliosis.A positive serology is not a confirmation of ocular Lyme disease.We followed five cases with uveitis and a positive Lyme serology that had negative anterior chamber antibody ratios (Goldmann-Witmer coefficient) and for whom the diagnosis was finally sarcoidosis.Patients with a compatible clinical picture and positive ACE & lysozyme tests in presence of cutaneous anergy have a probability of over 95% to have ocular sarcoidosis.9